The acetylation of histone lysine is central for providing the dynamic regulation of chromatin-based gene transcription. The bromodomain (BRD), which is the conserved structural module in chromatin-associated proteins and histone acetyl-tranferases, is the sole protein domain known to recognize acetyl-lysine residues on proteins.
The BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRDT) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction. BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al., Mol. Cell., 2008, 30(1):51-60), while BRD4 appears to be involved in the recruitment of the pTEF-[beta] complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al., Cell, 2009, 138(1): 129-145). It has also been reported that BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or BRD3-NUT, in a highly malignant form of epithelial neoplasia (French et al., Cancer Research, 2003, 63, 304-307 and French et al., Journal of Clinical Oncology, 2004, 22 (20), 4135-4139). Data suggests that BRD-NUT fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27, 2237-2242). BRD-t is uniquely expressed in the testes and ovary. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al., Cell, 2004, 1, 17(3), 349-60).
Japanese patent application JP 2008-156311 discloses a benzimidazole derivative which is said to be a BRD2 bromodomain binding agent which has utility with respect to virus infection/proliferation.
International patent application WO 2009/084693 discloses a series of thienotriazolodiazepiene derivatives that are said to inhibit the binding between an acetylated histone and a bromodomain containing protein and are said to be useful as anti-cancer agents.
International patent application WO 2011/054846 discloses a series of quinoline derivatives that inhibit the binding of BET family bromodomains with acetylated lysine residues.
Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT consists of tandem bromodomains. These domains are frequently referred to as BD1 (first bromodomain) and BD2 (second bromodomain) respectively and they share a high sequence homology. Lack of availability of potent and selective inhibitors have hindered the progress of dissecting biology of such bromodomain selective BET inhibitors. Selective targeting of either of these BD domains might pose different therapeutic profile over the pan BET inhibitors.
There remains a need for potent bromodomain inhibitors with desirable selectivity and pharmaceutical properties. Certain spiro[cyclobutane-1,3′-indolin]-2′-one derivatives have been found according to the present invention which inhibit the binding of BET family bromodomains to acetylated lysine residues. Such compounds will hereafter be referred to as “bromodomain inhibitors”.